Exploring the Multi–Target Neuroprotective Chemical Space of Benzofuran Scaffolds: A New Strategy in Drug Development for Alzheimer’s Disease

Cabrera‐Pardo, Jaime R.; Fuentealba, Jorge; Gavilán, J. F.; Cajas, Daniel; Becerra, José; Napiórkowska, Mariola

doi:10.3389/fphar.2019.01679

Cited by 14 publications

(8 citation statements)

References 65 publications

(97 reference statements)

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“…Our results aligned with this study, and it can be suggested that the selective activity might be related to the structure–activity relationship (SAR) of these phlorotannins to Aβ42 oligomers, notably to the fucofuroeckols containing the additional benzofuran ring compared with eckols. This is supported by previous studies demonstrating that benzofuran derivatives have neuroprotective properties against Aβ (Rizzo et al ., 2008; González‐Ramírez et al ., 2018; Lee & Byun, 2018; Cabrera‐Pardo et al ., 2020). González‐Ramírez et al .…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, Cabrera‐Pardo et al . (2020) explored the multi‐target neuroprotective potential of benzofuran scaffolds and suggested that privileged oxygen‐containing heterocycles such as benzofurans exert neuroprotection by inhibiting several important events involved in the AD process including cholinesterase, ROS stress and Aβ‐cell membrane binding (Rizzo et al ., 2008, 2012; Cabrera‐Pardo et al ., 2020). However, further in‐depth investigations with individual phlorotannins are required to confirm neuroprotective specificity and the chemico‐biological basis conferring neuroprotection.…”

Section: Discussionmentioning

confidence: 99%

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Neuroprotective activity of macroalgal fucofuroeckols against amyloid β peptide‐induced cell death and oxidative stress

Shrestha

Choi

Zhang

et al. 2022

Int J of Food Sci Tech

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Summary Phlorotannins are polyphenolic compounds predominantly found in brown seaweeds tentatively identified as having neuroprotective bioactivity; however, the effects of individual constituent phlorotannins against amyloid β neurotoxicity, the main hallmark neurotoxic protein in Alzheimer’s disease (AD), is yet to be fully characterised. In this study, four phlorotannins, namely eckol, dieckol, phlorofucofuroeckol‐A (PFFA) and 974‐A sourced from the brown seaweed Ecklonia species were assessed for their ability to protect against the toxic effects of H2O2, lipid peroxidation via tert‐butyl hydroperoxide (t‐BHP) and Aβ1–42 in neuronal PC12 cells. All compounds significantly scavenged reactive oxygen species (ROS). However, only PFFA and 974‐A protected PC12 cells from oxidative stress‐evoked neurotoxicity, providing significant increases in cell viability in response to both cytosolic (H2O2) and lipid peroxidation‐evoked (t‐BHP) cell stress. None of the phlorotannins tested inhibited Aβ1–42 aggregate morphology, which suggested that their neuroprotective activity was unrelated to direct interactions with Aβ1–42 protein. Our results indicate that while all phlorotannins tested exhibited ROS scavenging activity, only fucofuroeckol‐type phlorotannins such as PFFA and 974‐A afforded broader neuroprotective activity in response to both oxidative stress and amyloid β exposure. The additional amyloid‐protective capacity of fucofuroeckols reveals the potential importance of the benzofuran moiety in neuroprotection and further studies are encouraged to investigate the chemico‐biological basis of this distinction in the search for neuroprotective therapies in dementia and other neurodegenerative conditions.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Neuroprotective activity of macroalgal fucofuroeckols against amyloid β peptide‐induced cell death and oxidative stress

Shrestha

Choi

Zhang

et al. 2022

Int J of Food Sci Tech

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“…Attempts have been made to design and synthesize compounds that contain two distinct functional groups that each target a different pathway involved in AD ( Cabrera-Pardo et al, 2019 ; Bhatia et al, 2021 ). This can be achieved by the molecular hybridization of different pharmacophore moieties from already identified bioactive molecules ( Uddin et al, 2021 ).…”

Section: Multi-targets: An Unconventional Strategy For Alzheimer’s Di...mentioning

confidence: 99%

Multi-Targets: An Unconventional Drug Development Strategy for Alzheimer’s Disease

Chen

Dai

Liu

et al. 2022

Front. Aging Neurosci.

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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that eventually leads to dementia and death of the patient. Despite the enormous amounts of resources and efforts for AD drug development during the last three decades, no effective treatments have been developed that can slow or halt the progression of the disease. Currently available drugs for treating AD can only improve clinical symptoms temporarily with moderate efficacies. In recent years, the scientific community has realized these challenges and reconsidered the future directions of AD drug development. The most significant recent changes in AD drug development strategy include shifting from amyloid-based targets to other targets, such as tau, and efforts toward better designs for clinical trials. However, most AD drug development is still focused on a single mechanism or target, which is the conventional strategy for drug development. Although multifactorial mechanisms and, on this basis, multi-target strategies have been proposed in recent years, this approach has not been widely recognized and accepted by the mainstream of AD drug development. Here, we emphasize the multifactorial mechanisms of AD and discuss the urgent need for a paradigm shift in AD drug development from a single target to multiple targets, either with the multi-target–directed ligands approach or the combination therapy approach. We hope this article will increase the recognition of the multifactorial nature of AD and promote this paradigm shift. We believe that such a shift will facilitate successful development of effective AD therapies.

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“…The benzofuran skeleton can be found in numerous natural molecules [1][2][3] and bioactive compounds. 4,5 The clinical importance of these pharmacophores lies in the fact that they display potent biological properties including antioxidant, 1 antitubercular and antibacterial, 6,7 neuroprotective, 8 anti-inflammatory, 9 and antitumor 10 activities. Due to their diverse biological effects their derivatives are the main source of a great number of clinically approved drugs as well as drug candidates, such as antidepressants citalopram 11 and vilazodone 12 or antiarrhythmic agents amiodaron and dronedarone.…”

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confidence: 99%

Synthesis of 3-Aryl- and 3-Alkynylbenzofurans in the Presence of a Supported Palladium Catalyst

et al. 2022

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Suzuki and Sonogashira coupling reactions of 3-iodo-2-phenylbenzofuran, leading to the corresponding 3-aryl- and 3-alkynyl derivatives, respectively, were carried out using a silica supported pyridinium ionic liquid based heterogeneous catalyst. Under optimized reactions conditions, arylboronic acids with either electron withdrawing or -donating substituents as well as terminal alkynes with aromatic or aliphatic groups could be coupled to the benzofuran skeleton efficiently. The application of this catalyst made it possible to carry out the reaction under phosphine-free and, in case of the Sonogashira coupling, under copper-free conditions. The catalyst retained its activity in at least 7 subsequent runs in both types of reactions. Palladium leaching of less than 1% of the original amount used in the catalytic reaction was observed under optimized conditions in most cases. The methodology was applied successfully in the synthesis of nine different 3-aryl- and ten different 3-alkynyl benzofuran derivatives in moderate to high yields.

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Exploring the Multi–Target Neuroprotective Chemical Space of Benzofuran Scaffolds: A New Strategy in Drug Development for Alzheimer’s Disease

Abstract: against multiple events involved in AD. This benzofuran chemical framework will establish a multi-target chemical space that could set the basis for the development of super drugs against AD.

Cited by 14 publications

References 65 publications

Neuroprotective activity of macroalgal fucofuroeckols against amyloid β peptide‐induced cell death and oxidative stress

Neuroprotective activity of macroalgal fucofuroeckols against amyloid β peptide‐induced cell death and oxidative stress

Multi-Targets: An Unconventional Drug Development Strategy for Alzheimer’s Disease

Synthesis of 3-Aryl- and 3-Alkynylbenzofurans in the Presence of a Supported Palladium Catalyst

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